title: Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes.
abstract: Merozoites of malaria parasites invade red blood cells (RBCs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. Here, we report that a protein kinase-mediated signalling pathway involving host RBC PAK1 and MEK1, which do not have orthologues in the Plasmodium kinome, is selectively stimulated in Plasmodium falciparum-infected (versus uninfected) RBCs, as determined by the use of phospho-specific antibodies directed against the activated forms of these enzymes. Pharmacological interference with host MEK and PAK function using highly specific allosteric inhibitors in their known cellular IC50 ranges results in parasite death. Furthermore, MEK inhibitors have parasiticidal effects in vitro on hepatocyte and erythrocyte stages of the rodent malaria parasite Plasmodium berghei, indicating conservation of this subversive strategy in malaria parasites. These findings have profound implications for the development of novel strategies for antimalarial chemotherapy.
authors.affiliation: INSERM U609/Inserm-EPFL Joint Laboratory,Global Health Institute, Lausanne, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sicard
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Semblat
authors.forename: Caroline
authors.initials: C
authors.lastname: Doerig
authors.forename: Romain
authors.initials: R
authors.lastname: Hamelin
authors.forename: Marc
authors.initials: M
authors.lastname: Moniatte
authors.forename: Dominique
authors.initials: D
authors.lastname: Dorin-Semblat
authors.forename: Julie A
authors.initials: JA
authors.lastname: Spicer
authors.forename: Anubhav
authors.initials: A
authors.lastname: Srivastava
authors.forename: Silke
authors.initials: S
authors.lastname: Retzlaff
authors.forename: Volker
authors.initials: V
authors.lastname: Heussler
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Waters
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology* / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D020128:Inhibitory Concentration 50; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D010962:Plasmodium berghei / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D047428:Protein Kinase Inhibitors; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human